STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

Zhichuan Zhu; Xin Zhou; Hongwei Du; Erica W Cloer; Jiaming Zhang; Liu Mei; Ying Wang; Xianming Tan; Austin J Hepperla; Jeremy M Simon; Jeanette Gowen Cook; Michael B Major; Gianpietro Dotti; Pengda Liu

doi:10.1002/advs.202203718

STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

Adv Sci (Weinh). 2023 Jan;10(3):e2203718. doi: 10.1002/advs.202203718. Epub 2022 Nov 29.

Authors

Zhichuan Zhu^{1

2}, Xin Zhou^{1

3}, Hongwei Du^{1

3}, Erica W Cloer¹, Jiaming Zhang⁴, Liu Mei², Ying Wang^{1

2}, Xianming Tan^{1

5}, Austin J Hepperla^{1

6

7}, Jeremy M Simon^{1

6

7

8}, Jeanette Gowen Cook^{1

2}, Michael B Major⁹, Gianpietro Dotti^{1

3}, Pengda Liu^{1

2}

Affiliations

¹ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
² Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
³ Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁴ Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115, USA.
⁵ Department of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁶ Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁷ UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁸ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁹ Department of Cell Biology and Physiology, Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, 63130, USA.

Abstract

STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.

Keywords: 2-BP; STING; VDAC2; innate immunity-independent; mTORC1; mitochondrial homeostasis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Calcium / metabolism
Carcinoma, Renal Cell* / metabolism
Humans
Immunity, Innate
Kidney Neoplasms*
Mitochondria / metabolism
Reactive Oxygen Species / metabolism
Tumor Microenvironment
Voltage-Dependent Anion Channel 2 / metabolism

Substances

Calcium
Reactive Oxygen Species
VDAC2 protein, human
Voltage-Dependent Anion Channel 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding